Long-term Survivors Of Hematopoietic Cell Transplantation Research Articles

Psychoneurological symptoms, inflammatory biomarkers and gut microbiome richness and diversity in individuals receiving hematopoietic cell transplantation (HCT).

e24053 Background: Hematopoietic Stem Cell Transplantation (HCT) is a potentially curative treatment for certain hematologic cancers. Although survival rates are markedly higher than in the past, there are a growing number of long-term HCT survivors who are at risk for short and long-term sequela, which can negatively affect quality of life. Psychoneurological (PN) symptoms are common occurrences associated with heightened inflammation in other cancers and chronic conditions. Emerging research links the gut microbiota to inflammatory biomarkers and suggests that gut-microbiota-brain crosstalk impacts the severity of psychoneurological symptoms among HCT recipients. Methods: This longitudinal descriptive study investigated the relationship among a cluster of PN symptoms (pain, fatigue, and depression), inflammatory biomarkers (IL-6, IL-10, C-reactive protein (CRP), and microbiota diversity measures (Shannon and Chao Beta diversity indexes) in 55 individuals receiving HCT for a hematologic malignancy. The time periods examined covered pre-transplant, 30-days, and 100-days following transplant. The PN symptoms were collected through self-reported questionnaires via computer with assistance from study staff, along with blood samples and stool specimens obtained at each study visit. Inflammatory marker values were log-transformed when used as dependent variables. Gut microbiota samples were analyzed using 16S ribosomal gene (V4 region) amplicons using Illumina MiSeq. Data analysis was performed using SAS 9.4, with PROC MIXED used for the mixed model analyses. Results: The analysis characterized mean changes in microbiota diversity over time for both Shannon and Chao indexes. IL6 levels were consistent over time, with an inverse association with Chao but not Shannon index. IL10 and CRP levels changed over time, but without associations with either Shannon or Chao. Pain severity and interference changed over time, but with no associations with inflammatory markers or gut microbiome beta diversity. Fatigue severity and interference changed over time and were positively associated with IL10. Depression did not change over time and was not associated with inflammatory markers or diversity. Conclusions: This study provides preliminary information related to associations between PN symptoms, inflammatory markers, and selected measures of gut microbiome diversity in HCT recipients. Further research is needed to explore and validate these findings to examine the implications for microbiota diversity on inflammatory factors and PN symptoms. Clinical trial information: NCT02398708 .

SCD Dyslipidemia Normalizes Long-Term Following Nonmyeloablative Hematopoietic Cell Transplantation

Dyslipidemia is common in patients with sickle cell disease (SCD). Individuals with SCD have a unique type of dyslipidemia. This SCD dyslipidemia (hypocholesterolemia subtype) is characterized by low total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c), and normal triglycerides (TG). This SCD dyslipidemia state is theorized to be cardioprotective regarding atherosclerotic risk due to the hypolipidemic condition. Hematopoietic cell transplantation (HCT) is a potentially curative therapy for SCD. Nonmyeloablative HCT has been employed at the National Institutes of Health (NIH) and internationally with good results. Long-term survivors of HCT, specifically for hematologic malignancies, are at increased risk for dyslipidemia (hypercholesterolemia subtype), thus increasing atherosclerotic risk long-term. There are no studies investigating the short or long-term effects of HCT on SCD dyslipidemia. Therefore, we report a novel study to characterize lipid profiles at baseline and after HCT for SCD. This cohort study analyzes data from patients who received their first nonmyeloablative HLA-matched sibling or haploidentical HCT for SCD at the NIH from May 2009 to December 2021. All patients received sirolimus as GVHD prophylaxis. Total cholesterol, HDL-c, LDL-c, and triglycerides were collected pre-HCT, one-year post-HCT, and annually thereafter via a fasting serum-based lipid panel (median follow-up of 4 years). Data were analyzed using linear generalized estimating equation regression models to measure the influence of factors such as year of HCT, sirolimus use, gender, age, and graft failure on TC, LDL-c, HDL-c, and TG levels. A total of 116 patients were included in this analysis. There were 72 male and 44 female patients. The median age was 31 (range 10 to 64) years. 90% of the patients had Hb-SS, 3% Hb-SC, 5% Hb-Sβ 0, and 2% Hb-Sβ +. Overall survival is 87%, and 19% experienced graft failure. The median time on sirolimus post-HCT was one year. Baseline, one-year, and two-year mean (25th, 75th percentile) values, respectively, for the TC, LDL-c, HDL-c, and TG are as follows: TC [130.7 (107.0, 147.0), 183.2 (144.5, 220.0), 175.2 (144.5, 209.0)], LDL-c [72.5 (50.0, 87.0), 109 (73.5, 130), 104.2 (75.5, 128.0)], HDL-c [32.3 (23.8, 39.3), 49.4 (38.0, 55.5), 49.2 (41.5, 58.0)] and TG [127.3 (88.5, 156.5), 125.9 (87.0, 153.5), 112.6 (72.0, 133.5)]. Generally, the first-year post-HCT changes were maintained annually thereafter. (Figure 1). According to linear regression modeling, the change in TC, LDL-c, HDL-c, and TG at one-year post-HCT was +50.3 mg/dL (p<0.0001), +36.4 mg/dL (p <0.0001), +20.4 mg/dL (p<0.0001) and -26.5 mg/dL (p<0.0001), respectively. For failed grafts, the estimated changes after one-year post-HCT in TC, LDL-c, HDL-c, and TG were +6.5 mg/dL (p=0.45), -2.1 mg/dL (p=0.78), +14.8 mg/dL (p<0.0001), and -28.0 (p=0.03), respectively. The use of sirolimus only resulted in a significant change in TG (+32.8 mg/dL (p = 0.004)). Age had statistically significant changes only on TC (+1.08 mg/dL for a one-year change in age, p=0.005) and LDL-c (+0.73 mg/dL for a one-year change in age, p=0.03). There were no significant differences in TC, LDL-c, HDL-c, and TG levels (p>0.05) based on gender and HCT type. To summarize, HCT with sustained grafts led to significant rises in TC, LDL-c, and HDL-c and a decline in TG from baseline to one-year post-HCT, resulting in the normalization of lipid profiles. These changes were maintained annually thereafter. Graft failure most notably resulted in TC and LDL-c level declines back to pre-HCT baseline (Figure 2), while HDL-c and TG levels did not completely revert to baseline values. Sirolimus effects were significant on TG levels alone. These findings suggest that the mechanism underlying SCD dyslipidemia is corrected with the reversal of SCD. Long-term follow-up studies are indicated to assess patients' risk for atherosclerosis and adverse cardiac outcomes.

Association of Self-Reported COVID-19 Vaccination Status with COVID-19 Infection among Adult Long-Term Hematopoietic Cell Transplantation Survivors

Hematopoietic cell transplantation (HCT) recipients experience significant morbidity and mortality from coronavirus disease 19 (COVID-19) infection. Data are limited regarding long-term HCT survivors' uptake of and experiences with COVID-19 vaccination and infection. This study aimed to characterize COVID-19 vaccination uptake, use of other prevention measures, and COVID-19 infection outcomes in adult HCT recipients at our institution. Between July 1, 2021, and June 30, 2022, long-term adult HCT survivors were surveyed regarding overall health, chronic graft-versus-host (cGVHD) status, and experiences with COVID-19 vaccinations, prevention measures, and infections. Patients reported COVID-19 vaccination status, vaccine-related adverse effects, use of nonpharmaceutical prevention measures, and infections. Comparisons by response and vaccination status were performed using the chi-square test and Fisher exact test for categorical variables and the Kruskal-Wallis test for continuous variables. Of 4758 adult HCT survivors who underwent HCT between 1971 and 2021 and consented to participate in annual surveys, 1719 (36%) completed the COVID-19 module, and 1598 of 1705 (94%) reported receiving ≥1 dose of COVID-19 vaccine. Severe vaccine-related adverse effects were infrequent (5%). Among respondents receiving an mRNA vaccine, completion of doses according to the Centers for Disease Control and Prevention's vaccine recommendations at the time of survey return was 2 doses in 675 of 759 (89%), 3 doses in 610 of 778 (78%), and 4 doses in 26 of 55 (47%). Two hundred fifty respondents (15%) reported COVID-19 infection; 25 (10%) required hospitalization. Vaccinated respondents reported significantly higher uptake of household vaccination (1284 of 1404 [91%] versus 18 of 88 [20%]; P < .001) and the use of nonpharmaceutical interventions (P < .001). Among those vaccinated prior to infection, vaccinated respondents were significantly less likely to have contracted COVID-19 (85 of 1480 [6%] versus 130 of 190 [68%]; P < .001), as were their household members (149 of 1451 [10%] versus 85 of 185 [46%]; P < .001). Receipt of additional COVID-19 vaccine doses beyond the first dose was associated with a reduced risk of COVID-19 infection (odds ratio, .63; 95% confidence interval, .47 to .85; P = .002). Vaccination was well tolerated and associated with a lower risk of COVID-19 infection among HCT survivors and their household contacts. Vaccination and booster doses should be encouraged as part of a multifaceted approach in this high-risk population.

Feasibility of implementing a supervised telehealth exercise intervention in frail survivors of hematopoietic cell transplantation: a pilot randomized trial

BackgroundPatients undergoing hematopoietic cell transplantation (HCT) are at high risk of chronic health complications, including frailty and physical dysfunction. Conventional exercise programs have been shown to improve frailty in other cancer populations, but these have largely been based out of rehabilitation facilities that may act as geographic and logistical barriers. There is a paucity of information on the feasibility of implementing telehealth exercise interventions in long-term HCT survivors.MethodsWe conducted a pilot randomized trial to assess the feasibility of an 8-week telehealth exercise intervention in 20 pre-frail or frail HCT survivors. Participants were randomized to either a telehealth exercise (N = 10) or delayed control (N = 10). We administered a remote physical function assessment at baseline, followed by an 8-week telehealth exercise intervention (30-60 min/session, 3 sessions/week), and post-intervention. The primary endpoint was feasibility as determined by 1) > 70% of participants completing all remote physical functional assessments, and 2) > 70% of participants in the exercise group completing > 70% (17/24) of the prescribed exercise sessions. Exploratory outcomes included changes in gait speed, handgrip strength, and short physical performance battery.ResultsThe mean [standard deviation] age at study enrollment was 64.7 [9.1] years old. Twelve had undergone allogenic and 8 had undergone autologous HCT at an average of 17 years from study enrollment. Both feasibility criteria were achieved. Nineteen patients (95%) completed all remote study outcome assessments at baseline and post-intervention, and nine participants in the exercise group completed > 70% of prescribed exercise sessions. Overall, no significant group x time interaction was observed on handgrip strength, fatigue, body mass index, and short physical performance battery test (P < 0.05). However, there were significant within-group improvements in four-meter gait speed (+ 13.9%; P = 0.004) and 5-minute gait speed (+ 25.4%; P = 0.04) in the exercise group whereas non-significant changes in four-meter gait speed (-3.8%) and 5-minute gait speed (-5.8%) were observed after 8 weeks.ConclusionImplementing an 8-week telehealth exercise intervention for long-term HCT survivors was feasible. Our findings set the stage for innovative delivery of supervised exercise intervention that reduces the burden of frailty in HCT survivors as well as other at-risk cancer survivors.Trial registrationThe protocol and informed consent were approved by the institutional IRB (IRB#20731) and registered (ClinicalTrials.gov NCT04968119; date of registration: 20/07/2021).

Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy

Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P=.001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P=.006), but not SN (HR, 1.30; 95% CI, .73 to 2.31; P=.38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P=.0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P=.0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P=.0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.

Long-term patient-reported neurocognitive outcomes in adult survivors of hematopoietic cell transplant

AbstractSurvivors of hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can negatively affect quality of life. Given limited studies, we aimed to describe the neurocognitive outcomes in a cohort of long-term adult HCT survivors. Eligible survivors (age ≥21 years at HCT and alive ≥2 years following HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL) and the Childhood Cancer Survivor Study Neurocognitive Questionnaire (NCQ). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Survivors (n = 1861, 47.7% female, 65.6% allogeneic HCT) were surveyed at a median age of 64.2 years (interquartile range [IQR], 56.8-70.5) and a median 12.0 years (IQR, 6.0-21.0) from HCT. Survivors reported average Neuro-QoL scores (50.0 allogeneic; 49.2 autologous survivors) compared with an expected mean of 50 in the general population. On the NCQ, 17.4% to 31.2% of survivors reported impairments (Z-score >1.28) in task efficiency, memory, emotional regulation, or organization, compared with an expected 10% in the general population (all P < .01). In multivariable regression analyses, impaired Neuro-QoL (T-score <40) was independently associated with hearing issues (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.46-3.10) and sleep impairment (OR, 4.41; 95% CI, 2.80-6.94) among allogeneic survivors, with comparable associations in autologous survivors. Overall, long-term adult HCT survivors reported average cognitive quality of life compared with the general population. Subsets of survivors with hearing issues and sleep impairments were more likely to report lower quality of life and impaired neurocognitive function, which may facilitate targeted monitoring or interventions following HCT.

Community Health Status and Long-Term Outcomes in 1-Year Survivors of Autologous and Allogeneic Hematopoietic Cell Transplantation

Background: Race/ethnicity and socioeconomic status (SES) have been associated with access to and outcomes after hematopoietic cell transplantation (HCT). The role of health disparity factors beyond race/SES in HCT outcomes, however, has not been well described. This is especially true for long-term HCT survivors, for whom local socio-demographic factors may have a greater impact on outcomes because patients may no longer be under close monitoring of their transplant center. The County Health Rankings and Roadmaps (CHRR) provides updated aggregated information from several publicly available datasets to comprehensively describe the health status of US counties. A recent report demonstrated an association between community health status and 1-year non-relapse mortality in a CIBMTR cohort of allogeneic HCT recipients (Hong et al., Cancer 2021). We conducted a single-center retrospective cohort study to investigate the association between community health and long-term outcomes in 1-year autologous and allogeneic HCT survivors.Methods: Our study included 1,812 consecutive adult patients from Cleveland Clinic's BMT Program database who received their first allogeneic or autologous HCT between 2003 and 2017 and survived at least 1 year after their transplant. We used patient community risk score (PCS) as the surrogate for community health. PCS was nationally standardized and calculated as the sum of weighted Z-scores of the 23 county-level community health factors considered in CHRR. The 23 factors fell under 4 categories of health factors: health behavior (tobacco and alcohol use, etc.), clinical care (access and quality of care), social and economic factors (education, community safety, etc.), and physical environment (environmental quality and built environment). Higher PCS indicate worse community health. We evaluated the association of PCS with overall survival (OS), relapse, and non-relapse mortality (NRM) with Cox or Fine and Gray regression separately for autologous and allogeneic HCTs. Considered co-variables included pre-transplant sociodemographic data, disease diagnosis, and transplant factors.Results: Autologous HCT recipients (n=1,313) lived in 133 of 3,141 CHRR counties, 90% in Ohio. Similarly, allogeneic recipients (n=499) were from 88 counties, 88% in Ohio. Patient characteristics are shown in Table 1. The median (range) PCS scores for autologous and allogeneic HCT recipients were 0.03 (-0.85, 0.97) and 0.03 (-0.85, 0.58), respectively. For comparison, the PCS for the complete US CHRR dataset ranged from -1.43 to 2.54 and ranged from -1.6 to 2.0 in the prior CIBMTR study that included allogeneic HCT recipients (Hong et al., Cancer 2021). PCS was not associated with OS, relapse, or NRM for autologous or allogeneic HCT recipients in univariable analysis, nor were the four categories of health factors that contribute to the total PCS (Table 2). In addition, race and estimated median household income were not associated with mortality. Similar findings were noted in multivariable analysis.Conclusion: In our single center study, PCS was not associated with OS, relapse, or NRM in allogeneic or autologous HCT recipients who survived at least 1 year after HCT. A limitation of our analysis is that our cohort represented a single center with regional representation, where long-term follow up care is provided through a dedicated survivorship clinic and there is a strong emphasis on psychosocial support. A national cohort with greater geographical diversity is needed to better define the association of community factors and outcomes in long-term HCT survivors. [Display omitted] DisclosuresHamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

Disability Associated with Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Chronic graft-versus-host disease (cGVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) and is associated with poor quality of life (QoL) and functional status among long-term HCT survivors. Disability is defined as any physical or mental impairment that limits a person's ability to do certain activities or interact with their environment. There are limited data regarding the association of cGVHD and disability. The aim of this study is to define disability and further understand contributing factors in patients with cGVHD.The Living With cGVHD Patient Survey was a cross-sectional online survey administered from May to August 2020 to US adult patients who reported a cGVHD diagnosis within the previous 5 years. Participants were recruited through patient advocacy groups and online patient panels. Respondents reported demographics, disease diagnosis, work status, cGVHD symptoms per Lee Symptom Scale (LSS), and impact on activities of daily living. Descriptive and correlational analyses were used to inform 3 composite definitions of disability: (1) severe cognitive disability (any report of severe limitation [>7 on a 0-10 scale] concerning managing personal finances, social interaction, or computer use); (2) severe physical disability (any report of severe limitation concerning personal hygiene; dressing; eating; or ability to use the restroom, move around the house, prepare meals, shop, do housework, or get around outside the home); and (3) work disability (any report of taking disability leave or leaving a job because of cGVHD).Out of 165 total survey respondents, 28 reported being retired, self-employed, or a homemaker and were excluded from the analysis as they were not considered part of the potentially employable general workforce (N=137). There were no demographic or cGVHD differences between respondents included in the study cohort vs those who were excluded.Nearly half of respondents (47%) reported severe cognitive limitations in at least 1 of the activities of the composite score (Figure 1). Univariable analyses demonstrated that cGVHD severity/duration (P=0.0056); LSS eye (P=0.0266), mouth (P=0.0132), lung (P=0.0002), skin, nutrition, energy, and psychological symptoms (P<0.0001 for all); and number of treatments (P=0.0210) and specialists seen (P=0.0030) were all associated with self-reported severe cognitive disability. Skin and psychological symptoms and number of specialists seen remained significant in a multivariable analysis (Table 1).Two-thirds (67%) of respondents reported severe physical disability associated with cGVHD (Figure 1). In univariable analyses, cGVHD severity/duration (P=0.0003); LSS skin (P=0.0112), eyes (P=0.0107), psychological (P=0.0003), mouth, lungs, nutrition, energy symptoms (P<0.0001 for all); and number of treatments (P=0.0323) and specialists seen (P=0.0275) were associated with physical disability. In a multivariable analysis, female sex and energy, mouth, and nutrition symptoms were found to be significant (Table 1).Nearly two-thirds of respondents (63%) reported work disability (Figure 1). In univariable analyses, non-White race (P=0.0248); cGVHD severity/duration (P=0.0220); LSS skin (P=0.005), eyes (P=0.0239), mouth (P=0.0222), lungs (P=0.0011), nutrition (P=0.0010), energy (P<0.0001), and psychological symptoms (P=0.0014); and number of specialists seen (P=0.0495) were associated with work disability. Results from a multivariable analysis confirmed race and energy to be factors significantly associated with work disability (Table 1).A substantial proportion of survey respondents reported severe cognitive and physical disability, as well as work-related disability, associated with cGVHD, highlighting the importance of defining and better understanding cGVHD-associated disability. Additional investigations of the impact of work type, sex and racial disparities, and specific cGVHD symptoms are needed to further understand this relationship and improve the overall health-related QoL of long-term HCT survivors. [Display omitted] DisclosuresHamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Williams: Incyte Corporation: Other: Employee of IQVIA, the company commissioned by Incyte Corporation to conduct this study. Flore: Incyte Corporation: Other: Employee of IQVIA, the company commissioned by Incyte Corporation to conduct this study. Galvin: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Turnbull: Incyte Corporation: Other: Employee of IQVIA, the company commissioned by Incyte Corporation to conduct this study. Yu: Incyte Corporation: Current Employment, Current holder of individual stocks in a privately-held company.

Mobility and Muscle Strength in Recipients of Hematopoietic Cell Transplantation for Sickle Cell Disease: A Preliminary Report from Sickle Transplant Evaluation of Longterm and Late Effects Registry (STELLaR)

IntroductionRecipients of Hematopoietic Cell Transplantation (HCT) are at risk for treatment related late effects including cardiovascular disease and diabetes. Physical fitness including mobility and muscle strength are important predictors of cardiovascular health and quality of life. Physical fitness has been described in children and adults who are long term survivors of HCT for malignant disease [1]. Patients with sickle cell disease (SCD) are likely to be subject to unique morbidity post-HCT as a consequence of the pathophysiology of SCD which is characterized by anemia, inflammation, pain, bone infarcts and neurological complications. A systematic assessment of physical fitness is required to understand some of the long-term outcomes HCT for SCD.MethodsWe enrolled patients with SCD ≥ 1-year post-HCT in Sickle Transplantation Evaluating Long Term And Late Effects Registry (STELLaR). We assessed physical fitness including mobility using the timed up and go (TUG) test, and muscle strength using the handgrip strength (HGS) test. TUG scores were compared with published normative data for children (mean 9.2s; SD = 0.8) and young adults (mean 10.5s, SD = 1.1) [2]. TUG scores ≥ mean+ 2SD were considered abnormal (children: ≥10.8s, young adults ≥12.7s). The HGS of each patient was compared to published normative data of children and adults [3,4]. Patients ≤12 years were abnormal if they had a HGS of two standard deviations below the mean. Patients ≥13 years were considered abnormal if they had a HGS lower than the lower limit of the 85% age-sex standard. Additionally, patients were also assessed for chronic graft versus host disease (cGvHD) by means of the Lee Chronic GvHD Symptom Scale [5]. Patients rated their extent of being bothered by cGvHD symptoms on a scale from 1 to 5, with 1 being not at all and 5 being extremely. These scores were then organized into 7 categories of cGVHD symptoms and normalized to a 0-100 scale. We report the results of an interim analysis of physical fitness in these HCT recipients.ResultsOut of 121 patients enrolled in the study, 37 HCT recipients were assessed for mobility using the TUG test, and for muscle strength using the HGS test. Children were defined as being below the age of 18 and young adults between 18 and 40 years of age. Patient demographic and clinical results for TUG and HGS are presented in Table 1. Young adult participants were more likely to have abnormal TUG and HGS results than pediatric study participants. Patient self-reporting of overall (summary) cGvHD symptoms was found to be statistically significant between children and young adults (p=0.037) with young adults iappearing to be slightly more bothered by GvHD symptoms. There was no correlation in length of time in years between a patient's transplant and whether or not there was abnormal physical fitness (TUG and HGS) for both the young adult and children cohorts.ConclusionsThese data suggest the existence of impaired physical fitness in the long term in SCD patients who are HCT recipients. They provide the rationale for systematic evaluation of physical fitness and other risk factors for cardiovascular disease post-HCT.

Long-Term Quality of Life after Hematopoietic Cell Transplantation for Sickle Cell Disease: A Preliminary Report from the Sickle Cell Transplant Evaluation of Long Term and Late Effects Registry (STELLAR)

▪Introduction: Sickle cell disease (SCD) is characterized by unpredictable, recurrent acute and chronic persistent pain, and progressive organ damage leading to substantial morbidity, impaired quality of life and increased healthcare utilization. Hematopoietic cell transplantation (HCT) is the only therapy for SCD with curative intent. HCT is associated with excellent overall and event free survival especially in young children undergoing HCT from HLA identical family donors. Given these outcomes and improved supportive care, HCT is increasingly being offered to adults with SCD. However, a paucity of data exists on health related quality of life (HrQoL) in patients who are long term survivors of HCT. Therefore, a clear need exists to study HrQoL in children and adults post HCT to determine the long term benefit of HCT for SCD. We report the results of an interim analysis of HrQoL in recipients of HCT for SCD.Methods: We enrolledchildren and adults with SCD ≥ 1-year post-HCT in the Sickle Cell Transplant Evaluation of Long Term and Late Effects Registry (STELLAR). We obtained patient self-report of health status and health practices using a web based platform. Individuals under age 18 years and/or proxies completed Patient Reported Outcome Measurement Information System (PROMIS) version 25. Individuals over age 18 completed PROMIS version 29. Surveys were completed at enrollment and annually thereafter. T-scores were calculated for each survey domain. HrQoL in children (PROMIS25) and adults (PROMIS29) was compared to age appropriate norms (mean 50 ± 10). Univariate analysis was performed by age, gender, marital status, time from transplant, history of preHCT stroke, frequency of pain, number of emergency department (ED) visits, length of stay, income, and education assessed at the time of PROMIS survey administration. Statistical analysis was conducted using SAS Version 9.4. Descriptive statistics for each variable were reported. For numeric covariates, the mean and standard deviation (SD) were calculated and presented with frequency and its percentage shown for category variables. For repeated measures, generalized estimating equation (GEE) model was performed to detect the association. The significance level was set at 0.05.Results: Twenty-seven individuals completed 30 PROMIS25 surveys and 15 individuals completed 19 PROMIS29 surveys from 2017-2021. The mean age at transplant was 11.4years (SD 3.1) and 23.8 years (SD 6.2) in adults, respectively. Sixty percent and 50%, respectively, were female. The mean time from transplant was 4.2 years (SD 3.9) and 9.1 years (SD 7.1), respectively. Physical function/mobility, anxiety, depression, fatigue, and pain T-scores for each PROMIS measure are reported below in Table 1. Univariate analysis of PROMIS25 T-scores showed a statistically significant difference in anxiety by age and peer relationships by age, gender, and time from transplant. Time from transplant also had a statistically significant association with pain interference. PROMIS29 T-scores also showed a statistically significant difference in anxiety by age. Gender had a statistically significant association with depression and fatigue. Number of ED visits had a significant association with physical function, depression, social participation, and pain interference (Table 2). Other covariates lacked a statistically significant association or had insufficient sample sizes for comparison.Conclusions: Long-term HrQoL after HCT for SCD is within population norms for adults and children, though children have better HRQoL compared to adults. Better scores in females suggests the need for study of gender as a mediator of HrQoL outcomes. The observed relationship between HrQoL domains and education, income, time from transplant, and number of ED visits, a surrogate for healthcare utilization, suggest the need for careful study of these and other factors that can influence HrQoL post HCT over the long-term. In addition, further research in patient reported outcomes has the potential to identify needed areas of intervention and surveillance for this population. [Display omitted] DisclosuresGuilcher: Project Sickle Cure Study: Other: Principal Investigator, Research Funding; BlueBirdBio: Research Funding.

Incidence and Risk Factors for De Novo Cutaneous Squamous Cell Carcinoma in a Contemporary Cohort of Long-Term Hematopoietic Cell Transplantation Survivors

Improvement in hematopoietic cell transplantation (HCT) strategies and supportive care have contributed to a growing number of long-term survivors. Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer in these HCT survivors, and there are reported associations with immunosuppressive therapies (e.g., calcineurin inhibitors); antifungals (e.g., voriconazole); and post-HCT complications, such as chronic graft-versus-host disease (GVHD) (Kuklinski et al., 2017). That said, previous studies have included patients primarily treated during earlier transplant eras and have not accounted for changing patterns in HCT practice, such as improved GVHD prophylaxis and management, greater utilization of nonmyeloablative conditioning, and increasing numbers of HCTs performed in older individuals (D’Souza et al., 2020) who may be at higher risk of cSCC at baseline.

Social support as a moderator of healthcare adherence and distress in long-term hematopoietic cell transplantation survivors.

Treatment with hematopoietic cell transplantation (HCT) has potentially severe effects on physical and psychosocial functioning. Poor social support has been linked with physical morbidity and mortality as well as psychological distress in HCT survivors. This study tested a theory-driven hypothesis that social support buffers adverse effects of health stressors of comorbidities and graft-versus-host disease (cGVHD) on distress and adherence to recommended healthcare among long-term HCT survivors. This cross-sectional study analyzed baseline data from a randomized controlled trial in adult survivors 3-18years post-HCT. Data included medical records and patient-reported outcomes including cancer and treatment distress (CTXD), healthcare adherence (HCA), comorbidity index, cGVHD, ENRICHD Social Support Instrument (ESSI), Social Activity Log, and Health Self-Efficacy. We tested hypothesized models for HCA and CTXD using blocked hierarchical linear regressions. Among the 781 HCT survivors completing baseline assessment, 38% had > 3 comorbidities, 8% had moderate-severe cGVHD, 30% reported low social support, 30% reported elevated distress, and 49% reported low healthcare adherence. Social support and self-efficacy were directly related to both adherence and distress. Regression models supported the hypothesized moderated relationships for distress but not for healthcare adherence. The two tested models confirm that the health stressors of comorbidities and cGVHD are moderated by better social support and self-efficacy in their associations with lower distress but without moderating effects for healthcare adherence. Social support and self-efficacy confer protective benefits on healthcare adherence and psychological distress. Interventions are needed that focus on maintaining social networks or finding new networks if necessary. NCT00799461.

Incidence and Risk Factors of Late-Occurring Infections in a Contemporary Cohort of Hematopoietic Cell Transplantation Survivors

<h3>Introduction</h3> There is a paucity of information on late-occurring (≥1y) infectious complications in contemporary survivors of hematopoietic cell transplantation (HCT). Addressing these knowledge gaps can help tailor post-HCT infection surveillance and proactive immune reconstitution practices in this growing population. <h3>Method</h3> Patients were eligible if they underwent a first HCT at City of Hope between 2010 and 2013, and were alive and in remission at 1y post HCT; 696 were eligible and included in this study. Standardized (national guidelines) definitions were used to determine the occurrence of late-occurring (≥1y after HCT) severe/life-threatening/fatal bacterial, viral and fungal infections. Infections that occurred within 4 weeks of a previous one were considered polymicrobial. Follow-up was censored at relapse, subsequent malignancy, death, or December 31, 2017, whichever occurred first. Chronic GVHD (cGVHD) was categorized as none, mild, moderate/severe at 1y post HCT. We determined the cumulative incidence of: first, polymicrobial, vaccine-preventable, and subsequent infection (>4 weeks from initial infection), taking into consideration competing risk. We used multivariable regression (hazard ratio [HR], 95% confidence interval [CI]) to adjust for relevant covariates. <h3>Results</h3> Median age at HCT was 53.3y (range, 0.7y-78.1y); 58.5% were male; 73.1% were non-Hispanic white; 57.2% underwent allogeneic HCT; 42.8% were at high risk of relapse; 69.1% received myeloablative conditioning. Overall, 194 (27.9%) developed a late infection; 75 (10.8%) had at least one vaccine-preventable infection. Median time to first infection was 1.8y (range, 1.0-6.6y) from HCT. The 5y cumulative incidence of a late infection was 28.6%; 5y incidence of vaccine-preventable infection was 11.7%; 5y incidence of polymicrobial infection was 6.4%; and there was a steep increase in the incidence of each subsequent infection (Fig 1). Survivors of allogeneic HCT had a significantly higher 5y incidence (Fig 2), and the incidence was highest in patients with moderate/severe cGVHD at 1y post-HCT (Fig 3). Overall, there was a four-fold risk among allogeneic compared to autologous patients (HR 4.11; 95%CI 2.83-5.97; p<0.001). Mild cGVHD at 1y was associated with a 1.96-fold (95% CI 1.06-3.61) risk, while moderate/severe cGVHD was associated with a 3.61-fold (95% CI 1.98-6.58) risk of developing a late-occurring infection (reference: no cGVHD). <h3>Conclusion</h3> Nearly one third of long-term HCT survivors developed a severe/life-threatening/fatal infection, and one in ten developed a vaccine-preventable infection. Allogeneic HCT survivors had a higher risk than autologous survivors, due in part to cGVHD and its management. There was a steep increase in risk of subsequent infections with each infectious episode, emphasizing the need for closer monitoring and prevention strategies in these patients.

Cardiovascular Disease Risk Assessment and Management in Survivors of Allogeneic Hematopoietic Cell Transplantation

Long-term survivors of allogeneic hematopoietic cell transplantation (HCT) are at greater risk for developing late effects, with increased risk of mortality compared to the general population. This includes a 2-3 fold increased risk of metabolic syndrome and cardiovascular disease. While screening and appropriate treatment for metabolic syndrome and CVD is recommended for long-term HCT survivors, specific guidelines in this high risk population is limited. The Cleveland Clinic Blood and Marrow Transplant Survivorship program was established in 2016 to improve the long-term care of transplant recipients. Patients are systematically evaluated at 100 days, and 1-, 2-, and 5-years post-HCT by an advanced practice practitioner (APP) in a consultative model, in which the visit is primarily focused on health maintenance and late effects. In an effort to improve our practice of CVD screening and prevention, we created specific guidelines focusing on the 4 core clinical measures of metabolic syndrome: increased body weight/visceral adiposity, elevated lipids, increased blood pressure, and hyperglycemia/insulin resistance. Table 1 shows our survivorship programs approach to evaluating CVD risk in allogeneic HCT survivors and the subsequent preventive and management recommendations, that are based on American College of Cardiology/American Heart Association guidelines. The recommendations were further modified to account for common challenges providers identify in the unique HCT population, such as multiple HCT medication interactions, organ dysfunction and graft versus host disease. In addition, we encourage patients to follow up with their primary care providers to continue management and monitoring. Education is also provided on healthy lifestyle changes including exercise recommendations and healthy eating. Specific goals and targets are reviewed with patients and their caregivers. Dieticians, physical therapy, smoking and tobacco cessation are available and offered when appropriate. We present a platform for guideline-driven and multidisciplinary approach to assessment, prevention and management of CVD risk-factors in allogeneic HCT survivors. Data is being collected to evaluate the impact of medication, education and the systematic management of these patients and overall incidents of CVD events.

Trial in Progress: A Phase 3 Study of Itacitinib or Placebo in Combination with Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease (GRAVITAS-309)

Background Allogeneic hematopoietic cell transplantation (HCT) is indicated for several hematologic malignancies and nonmalignant disorders. Chronic graft-versus-host disease (cGVHD) develops in 30%-70% of long-term survivors of HCT and is a significant cause of nonrelapse mortality. Corticosteroids (CS) are the recommended first-line treatment for cGVHD; however, up to 60% of patients treated with CS require additional cGVHD therapy within 2 years. Furthermore, long-term exposure to CS is associated with a wide range of toxicities and increased risk of infection. Novel safe and effective therapies are needed to treat cGVHD and reduce CS dependence. Janus kinases (JAKs) mediate the signaling of proinflammatory cytokines involved in the pathogenesis of cGVHD. Itacitinib is a JAK-1 selective inhibitor that improved graft-versus-host disease (GVHD) and survival without affecting engraftment of donor leukocytes in murine models. In a phase 1 clinical study, itacitinib 200 or 300 mg once daily (QD) was well tolerated in patients with steroid-refractory or steroid-naive acute GVHD (aGVHD). Here we describe the trial design of the first clinical study evaluating the safety and efficacy of itacitinib for the treatment of cGVHD. Study Design and Methods GRAVITAS-309 (NCT03584516) is a 2-part phase 3 study of itacitinib or placebo in combination with CS as initial treatment for cGVHD. Patients aged ≥18 years who underwent allogeneic HCT from any donor type and graft source, with evidence of myeloid and platelet engraftment, and who have active, moderate, or severe cGVHD per National Institutes of Health Consensus Criteria are eligible to participate. Patients are excluded if they received &gt;1 prior HCT (except autologous), had &gt;3 days of systemic CS treatment for cGVHD, received any other systemic treatment for cGVHD, have presence of active uncontrolled infection, or had treatment with a JAK inhibitor within 8 weeks of randomization (patients who previously received a JAK inhibitor for aGVHD are eligible only if they achieved a complete or partial response). Part 1 is a randomized, open-label study to determine optimal dosing of itacitinib in combination with CS (~20 patients randomized 1:1 to itacitinib 200 mg QD or 300 mg QD; Figure 1). The primary endpoints for Part 1 are dose-limiting toxicities (DLTs) through Day 28 as well as clinical safety and laboratory assessments. Main secondary endpoints include pharmacokinetic (PK) parameters and efficacy outcomes (Table 1). After 20 patients have completed 28 days of treatment, an external data monitoring committee will review the data and provide a recommendation for an appropriate dose for Part 2 based on emergent adverse events, clinical laboratory parameters, PK data, and DLTs. Part 2 is a randomized, double-blind, placebo-controlled study using the dose selected in Part 1 to assess the efficacy and safety of itacitinib plus CS vs placebo plus CS (~246 patients stratified by cGVHD severity and randomized 1:1; Figure 1). Patients randomized to the placebo group will be permitted to cross over to the itacitinib group after completion of the primary analysis. The primary endpoint is overall response rate (proportion of patients with complete or partial response) at 6 months. Secondary endpoints include changes in symptom scores using health-related quality-of-life measures, additional efficacy outcomes, PK parameters, and clinical safety assessments (Table 1). Exploratory biomarker analyses will evaluate the effects of JAK inhibition on circulating inflammatory cells (ie, T-cell subsets, B cells, natural killer cells, cytokines) and biomarkers of GVHD in peripheral blood after transplant. Patients will remain on study for a total of 37 months, which includes treatment period, safety follow-up, and posttreatment GVHD follow-up, unless confirmed GVHD progression, start of a new GVHD therapy, or relapse/recurrence of underlying hematologic disease occurs earlier. Efficacy analyses will be performed on the intent-to-treat population; safety analyses will be conducted on all randomized patients who receive ≥1 dose of study drug. The PK-evaluable population will include all patients who receive ≥1 dose of study drug and provide ≥1 postdose plasma PK sample. Disclosures Morariu-Zamfir: Incyte Corporation: Employment. Bleam:Incyte Corporation: Employment. Yan:Incyte Corporation: Employment.

Late infectious complications in hematopoietic cell transplantation survivors.

7046 Background: Infections are a major complication of hematopoietic cell transplantation (HCT). Few studies have compared the incidence of late infections occurring ≥2y post-HCT to other cancer patients and the general population. Methods: Single center records of ≥2y HCT survivors who were Washington residents treated from 1992-2009 (n = 1,792; median age 46y; 53% allogeneic; 90% hematologic malignancies) were linked to the state’s hospital discharge and death registries. Individuals randomly selected from the state cancer registry (n = 5,455, non-HCT) and driver’s license files (n = 16,340, DOL) who survived ≥2y formed two comparison groups, matched on sex, age, year, and cancer diagnosis (non-HCT group only). Based on hospital and death registry codes, incidence rate ratios (IRR) with confidence intervals (CI) of infections by organism type and organ system were estimated using Poisson regression. Results: With 6y (range 2-20) median follow up, the incidence rate (per 1000 person-y) of all infections was 65 in HCT survivors vs. 40 in the non-HCT group (IRR 1.6, 95% CI 1.3-1.9). In contrast, the DOL group’s infection rate was 7 (HCT vs. DOL IRR 10.0, 95% CI 8.3-12.1). Specifically, bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRRs 1.7; p &lt; 0.01). Differences in viral infection rates were more modest (IRR 1.4, p = 0.07). Infections attributed to staphylococcus, streptococcus, and non-Candida fungi including Aspergillus were twice as common in the HCT vs. non-HCT cancer survivors (IRRs 2.1-2.3; p &lt; 0.05). IRRs for nervous system, respiratory, and musculoskeletal infections between these 2 groups were 1.9-2.8 (p &lt; 0.05). Among potentially vaccine-preventable organisms, the IRR was 3.2 (95% CI 2.2-4.6). While the absolute incidences decreased with time, the relative risks in almost all categories were even greater when restricted to ≥5y HCT vs. non-HCT cancer survivors. Conclusions: ≥2y HCT survivors had a significantly increased incidence of infections vs. matched non-HCT cancer survivors. Providers caring for long-term HCT survivors should maintain high vigilance for infections in this population and ensure adherence to HCT antimicrobial prophylaxis and vaccination guidelines.

Estimating Long-Term Survival in a Cohort of Allogeneic Hematopoietic Stem Cell Transplant Patients

Introduction: Allogeneic hematopoietic cell transplantation (HCT) is a common treatment for many hematologic diseases. Most deaths occur in the first 2 years after HCT due to relapse, graft-versus-host disease, infections, malignancies, or other toxicities. Among patients who are alive and recurrence free at 2 years after HCT, survival at 10 years is between 80% and 92%.Advances in transplantation practices have led to improved outcomes and more long-term HCT survivors. As survival outcomes continue to improve and new treatments emerge, understanding and quantifying the full lifetime benefit of HCT in terms of mean overall survival (OS) is clinically relevant. In this analysis, we estimate the mean OS of a cohort of HCT patients.Methods: A systematic literature review of all studies reporting OS post-HCT was conducted. Extracted data were incorporated into a long-term survival model using a step-wise approach: short-term survival (up to 2 years post-HCT) using data reported by Uhlin et al (Haematologica. 2014;99:346-52), and longer-term survival (more than 2 years post-HCT) using data reported by Wingard et al (J Clin Oncol. 2011;29:2230-9) and the age-adjusted life tables for the general UK population.Available published data provided OS estimates up to 15 years post-HCT, and beyond this time, OS estimates are uncertain. To estimate mean OS and address this uncertainty, three different survival scenarios were modeled: best-case, worst-case, and base-case. For the best-case, it was assumed that HCT patients were cured and had the same OS as the age-adjusted general population. For the worst-case, it was assumed that HCT patients carried excess mortality for the rest of their lives. The excess mortality was calculated from Wingard et al 2011, which showed 20% mortality from year 2-15 post-HCT; this is an order of magnitude greater than the general population (2%). For the base-case, a Weibull parametric function was fit to the data published by Wingard et al 2011 to estimate the survival curve from year 2 post-HCT until death. To incorporate the excess mortality, the lowest survival was chosen cycle over cycle between the parametric estimate and the age-adjusted life tables.Sensitivity analysis for the mean survival estimate was performed by fitting several different parametric functions using exponential, Gompertz, log-logistic, and log-normal. A lifetime analysis was undertaken for a cohort of patients starting at the weighted mean age at the time of HCT, calculated from Wingard et al 2011.Results: Only two published articles were found that provided OS in patients without complications after HCT (Uhlin et al 2014 and Wingard et al 2011). Data from Uhlin et al 2014 was used to estimate the percent alive at 2 years post-HCT, which was 65%.For a cohort of HCT patients that received their transplant at age 23.5, the estimated mean OS for the base-case was 25.9 years post-HCT, with parametric models ranging between 25.9 and 29.5 years. The best-case and worst-case estimates were 31.7 and 23.9 years, respectively.Conclusions: The mean OS for a cohort of HCT patients was estimated to be 25.9 years. This estimate helps to understand and quantify the full lifetime survival benefit to HCT patients, including the tail end of the survival curve, and the potential added benefits of future treatments post-HCT. The sensitivity analysis revealed a narrow range for the estimated mean OS, minimizing the uncertainty of the results. Our estimates are based on data published by Wingard et al 2011, which incorporates excess mortality after 2 years post-HCT. This is consistent with the clinical assumption that HCT patients continue to have excess mortality throughout their lifetime. Since the first 2 years post-HCT has the highest mortality rate, new treatments that can improve survival during this time may change the impact on the lifetime benefit of the therapy. DisclosuresPalmer:PRMA Consulting, Ltd: Consultancy. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership.

Changes in Glomerular Filtration Rate and Impact on Long-Term Survival among Adults after Hematopoietic Cell Transplantation: A Prospective Cohort Study.

Kidney injury is a significant complication for patients undergoing hematopoietic cell transplantation (HCT), but few studies have prospectively examined changes in GFR in long-term survivors of HCT. We described the association between changes in GFR and all-cause mortality in patients up to 10 years after HCT. We conducted a prospective, observational cohort study of adult patients undergoing HCT at the Fred Hutchinson Cancer Center in Seattle, Washington from 2003 to 2015. Patients were followed from baseline, before conditioning therapy, until a maximum of 10 years after transplant. We used Cox proportional hazard models to examine the association between creatinine eGFR and all-cause mortality. We used time-dependent generalized estimating equations to examine risk factors for decreases in eGFR. A total of 434 patients (median age, 52 years; range, 18-76 years; 64% were men; 87% were white) were followed for a median 5.3 years after HCT. The largest decreases in eGFR occurred within the first year post-transplant, with the eGFR decreasing from a median of 98 ml/min per 1.73 m2 at baseline to 78 ml/min per 1.73 m2 by 1 year post-HCT. Two thirds of patients had an eGFR<90 ml/min per 1.73 m2 at 1 year after transplant. When modeled as a continuous variable, as eGFR declined from approximately 60 ml/min per 1.73 m2, the hazard of mortality progressively increased relative to a normal eGFR of 90 ml/min per 1.73 m2 (P<0.001). For example, when compared with an eGFR of 90 ml/min per 1.73 m2, the hazard ratios for eGFR of 60, 50, and 40 ml/min per 1.73 m2 are 1.15 (95% confidence interval, 0.87 to 1.53), 1.68 (95% confidence interval, 1.26 to 2.24), and 2.67 (95% confidence interval, 1.99 to 3.60), respectively. Diabetes, hypertension, acute graft versus host disease, and cytomegalovirus infection were independently associated with a decline in GFR, whereas calcineurin inhibitor levels, chronic graft versus host disease, and albuminuria were not. Adult HCT recipients have a high risk of decreased eGFR by 1 year after HCT. Although eGFR remains fairly stable thereafter, a decreased eGFR is significantly associated with higher risk of mortality, with a progressively increased risk as eGFR declines.

Comparison of Chronic Graft-Versus-Host Disease Severity and Functional Status after Cord Blood, Haploidentical Related and 1-Allele Mismatched Unrelated Donor Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) can be accomplished with grafts from alternative donors for patients lacking an HLA-matched related or unrelated donor. The optimal choice of an alternative donor stem cell source remains an open question and is influenced by several factors including chronic graft-versus-host disease (cGVHD). Chronic GVHD is a heterogeneous syndrome with major morbidity and adverse effects on quality of life (QoL) among long-term allogeneic HCT survivors. The aim of this study was to analyze the incidence of cGVHD and manifestations associated with severe morbidity and poor functional outcomes among recipients with alternative HCT donors.Methods: This retrospective study included adults who received a first alternative donor HCT for any diagnosis between 2006 and 2015 in Seattle and subsequently developed cGVHD. The alternative grafts included unrelated 4-6/6-HLA-matched single or double cord blood units (UCB), related HLA-haploidentical bone marrow or mobilized blood stem cells with post-transplant cyclophosphamide (R-HAPLO), and mobilized blood cells from unrelated donors with 1-allele mismatching at an HLA-A, B, C or DR locus at any HLA-typing resolution (1-mMUD). Endpoints were cumulative incidence frequencies (CI) of cGVHD and the CI of manifestations associated with severe morbidity (i.e., grade 2 or 3 keratoconjunctivitis sicca, scleroderma-like skin features, grade 2 or 3 myofasciitis, bronchiolitis obliterans, or esophageal stricture requiring dilation) and the CI of functional outcomes (i.e., return to work/school after the diagnosis of cGVHD, discontinuation of systemic immunosuppressive therapy, and change in KPS). We also compared the 2014 NIH overall severity of cGVHD at initial diagnosis, the incidence of new systemic immunosuppression after first-line therapy for cGVHD, non-relapse mortality and overall survival after cGVHD diagnosis.Results: Of 396 alternative donor HCT recipients, 129 developed cGVHD and were included in this study. Chronic GVHD developed in 29 of 163 UCB recipients (3-year CI, 18%), 21 of 88 R-HAPLO recipients (24%) and 79 of 145 1-mMUD recipients (55%) HCT (Fig. 1A). The median follow-up times after onset of cGVHD were 48 (range 4-121) months for UCB, 60 (range <1-123) for R-HAPLO, and 46 (range 4-131) for 1-mMUD. Table 1 displays characteristics of cGVHD according to the alternative donor groups. The CI of any manifestation of severe morbidity at 3 years after a cGVHD diagnosis is shown in Fig. 1B and was significantly lower in UCB (14%) and R-HAPLO (23%) compared to the 1-mMUD group (58%) [hazard ratio (HR) 0.13 (95% Confidence Interval 0.1-0.4), p=<0.0001, and HR 0.31 (0.1-0.7), p=0.007, respectively]. Compared to the 1-mMUD group, a higher proportion of recipients of UCB (68% vs. 35%) returned to work/school at 3 years after cGVHD [HR 2.54 (1.1-5.7), p=0.02], and a similar trend was observed in R-HAPLO (62% vs. 35% [HR 2.38 (1.0-5.9), p=0.06)] (Fig. 1C). The CI of discontinued systemic immunosuppression at 3 years was significantly lower in the 1-mMUD (15%) compared to the UCB (45%) and R-HAPLO (50%) groups [HR 3.96 (1.9-8.4), p=0.0003, and HR 4.93 (2.2-11.1), p=0.0001, respectively], (Fig. 1D). We found trends suggesting improved annualized KPS change from cGVHD onset to 3.5 years in the UCB [+5 (range -12 to +44)] and R-HAPLO [+11 (range -14 to +64)] groups compared to the 1-mmUD group [0 (range -81 to +46)] (p=0.05 and p=0.06, respectively). The proportion of patients in each group requiring change in systemic therapy for control of cGVHD at 3 years after first line treatment was: 17% for UCB, 25% for R-HAPLO and 39% for 1-mMUD, and was significantly lower for UCB compared to the 1-mMUD group [HR 0.30 (0.1-0.8), p=0.01]. Non-relapse mortality and overall survival were similar among the 3 groups.Conclusions: Compared to 1-mMUD group, UCB and R-HAPLO HCT recipients were less likely to develop cGVHD. Among those with cGVHD, UCB and R-HAPLO HCT recipients were less likely to develop manifestations of severe morbidity, had less protracted cGVHD (a shorter duration of systemic treatment), and higher likelihood of resuming work or school, suggesting better QoL compared to 1-mMUD HCT recipients. Our results will help better counsel patients about alternative HCT donors. A randomized study (NCT01597778) comparing UCB with R-HAPLO HCT is underway to determine which of these donors may be associated with superior outcomes. [Display omitted] DisclosuresLee:Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Martin:Pfizer: Consultancy; Procter and Gamble: Equity Ownership; Incyte: Consultancy; Fresenius, Neovii: Research Funding. Cheng:Gilead Sciences, Inc.: Consultancy. Flowers:Pharmacyclics: Consultancy.

Recovery of Pulmonary Function after Allogeneic Hematopoietic Cell Transplantation in Children is Associated with Improved Survival

Abnormal pulmonary function is prevalent in survivors of allogeneic hematopoietic cell transplantation (HCT). Post-transplantation recovery of pulmonary function, and its effect on survival, in children are not known. This retrospective cohort study of 308 children followed for 10 years after HCT at a single institution included 2 groups of patients. Group 1 comprised 188 patients with 3 or more pulmonary function test (PFT) results, of which at least 1 was abnormal, and group 2 comprised 120 patients with 3 or more PFTs, all of which were normal. Pulmonary function normalized post-transplantation in 51 patients (27%) in group 1. Obstructive lung disease, restrictive lung disease, mixed lung disease, and normal pattern were seen in 43%, 25%, 5%, and 27% of patients, respectively, at a median of 5 years (range, 0.5 to 11.9 years) post-transplantation. Lung volumes recovered better than spirometric indices. Pulmonary complications were seen in 80 patients (43%) in group 1. Patients who recovered pulmonary function had better overall survival (P = .006), which did not differ significantly from that in patients in group 2 with normal lung function post-transplantation (P = .80). After adjusting for duration of follow-up, pulmonary complications (P = .01), and lower pretransplantation forced vital capacity z-scores (P = .01) were associated with poor recovery. T cell depletion (P < .001), lower pretransplantation forced expired volume in 1 second z-scores (P = .006), and chronic graft-versus-host disease (P < .001) increased the risk for pulmonary complications. Nonrecovery of lung function with pulmonary complications (P = .03), acute graft-versus-host disease (P = .004), and mechanical ventilation (P < .001) were risk factors for nonrelapse mortality. Normalization of pulmonary function is possible in long-term survivors of allogeneic HCT. Strategies to decrease the risk of pulmonary complications may improve outcomes.